ABC Triblock Terpolymers with Orthogonally Deprotectable Blocks: Synthesis, Characterization, and Deprotection

Article abstract of DOI:10.1021/acs.macromol.5b01823

The development and availability of new protecting groups are vital for all branches of synthetic chemistry. Equally vital is the facile and selective removal of these groups, leaving intact other protecting groups which are to be cleaved later. Herein we demonstrate this concept of orthogonal deprotection by combining three different forms of protected methacrylic acid (MAA) in the same terpolymers. One of these protected monomers was 2-(pyridin-2-yl)ethyl methacrylate (PyEMA), recently developed by us, whose units can be readily converted to MAA units either under alkaline hydrolysis conditions or thermally. The second monomer was tetrahydro-2H-pyran-2-yl methacrylate (THPMA) which can be cleaved either via acidic hydrolysis or by thermolysis. The third form of protected MAA was benzyl methacrylate (BzMA) which can be subjected to hydrogenolysis. Two ABC triblock terpolymers based on all three of these monomers were successfully synthesized-one by reversible addition-fragmentation chain transfer (RAFT) polymerization and the other by group transfer polymerization (GTP)-thus proving the feasibility of these demanding three-stage syntheses via both polymerization methods. The molecular weight characteristics and compositions of the terpolymers were determined by gel permeation chromatography and proton nuclear magnetic resonance spectroscopy (¹H NMR), respectively. Subsequently, the ABC triblock terpolymers were sequentially subjected to conditions of alkaline hydrolysis, acidic hydrolysis, and hydrogenolysis, leading to the selective cleavage of the PyEMA, the THPMA and the BzMA units, respectively, without affecting the remaining types of protecting groups, according to analysis using ¹H NMR spectroscopy. Similarly selective was the acidic hydrolysis followed by alkaline hydrolysis. Thermal treatment at 130 °C of the terpolymers led to the conversion of both the PyEMA and the THPMA units to MAA units, without affecting the BzMA units, yielding amphiphilic diblock copolymers whose self-assembly properties in water were investigated.

Full text of DOI:10.1021/acs.macromol.5b01823

Article
pubs.acs.org/Macromolecules
ABC Triblock Terpolymers with Orthogonally Deprotectable Blocks:
Synthesis, Characterization, and Deprotection
Marios Elladiou and Costas S. Patrickios*
Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
*
S Supporting Information
ABSTRACT: The development and availability of new
protecting groups are vital for all branches of synthetic
chemistry. Equally vital is the facile and selective removal of
these groups, leaving intact other protecting groups which are
to be cleaved later. Herein we demonstrate this concept of
orthogonal deprotection by combining three different forms of
protected methacrylic acid (MAA) in the same terpolymers.
One of these protected monomers was 2-(pyridin-2-yl)ethyl
methacrylate (PyEMA), recently developed by us, whose units
can be readily converted to MAA units either under alkaline
hydrolysis conditions or thermally. The second monomer was
tetrahydro-2H-pyran-2-yl methacrylate (THPMA) which can
be cleaved either via acidic hydrolysis or by thermolysis. The
third form of protected MAA was benzyl methacrylate (BzMA) which can be subjected to hydrogenolysis. Two ABC triblock
terpolymers based on all three of these monomers were successfully synthesizedone by reversible addition−fragmentation
chain transfer (RAFT) polymerization and the other by group transfer polymerization (GTP)thus proving the feasibility of
these demanding three-stage syntheses via both polymerization methods. The molecular weight characteristics and compositions
of the terpolymers were determined by gel permeation chromatography and proton nuclear magnetic resonance spectroscopy
1
(
H NMR), respectively. Subsequently, the ABC triblock terpolymers were sequentially subjected to conditions of alkaline
hydrolysis, acidic hydrolysis, and hydrogenolysis, leading to the selective cleavage of the PyEMA, the THPMA and the BzMA
1
units, respectively, without affecting the remaining types of protecting groups, according to analysis using H NMR spectroscopy.
Similarly selective was the acidic hydrolysis followed by alkaline hydrolysis. Thermal treatment at 130 °C of the terpolymers led
to the conversion of both the PyEMA and the THPMA units to MAA units, without affecting the BzMA units, yielding
amphiphilic diblock copolymers whose self-assembly properties in water were investigated.
INTRODUCTION
are poly(acrylic acid) (PAA) and poly(methacrylic acid)
PMAA), with major uses as adhesives and thickeners in the
■
(
The availability of protective groups is of utter importance in
organic chemistry, polymer chemistry, and biochemistry.
1
personal care, cosmetics, and pharmaceutical industries.
Furthermore, segments of PAA and PMAA constitute the
hydrophilic blocks of amphiphilic block copolymer surfactants,
also of industrial importance. In these surfactants, the
carboxylic acid moiety is introduced via the polymerization of
the corresponding protected monomer. Most of the carboxylic
acid protective groups in synthetic polymers are acid labile
Sometimes, the protection of a certain type of moiety using
different types of protective groups within the same molecule is
also necessary. These protective groups must be orthogonal,
i.e., be readily cleaved but under sufficiently different conditions
when required. This is most dramatically exemplified in solid
phase peptide synthesis, where at least three different types of
protecting groups for a given moiety (amine or carboxylic acid)
are required: a group protecting the terminal peptide moiety
attached to the resin, a group protecting one of the two
moieties (amine or carboxylic acid) of the incoming amino acid,
and a group protecting the functional side chain of the amino
6
−20
(
tertiary esters, trimethylsilyl esters, hemiacetal esters),
which are orthogonal with the less common hydrogenolysis-
1
0,21,22
sensitive (benzyl esters)
yl)
and photolabile (p-nitrophen-
2
3,24
protective groups. Surprisingly, there are almost no
literature examples of carboxylic acid protecting groups
cleavable under mildly basic conditions, with the exception of
2
,3
acid.
25−28
activated esters (pentafluorophenyl and succinimidyl)
As the structural complexity of synthetic polymers has ever
been increasing, with sequence-controlled polymers being a
representative example, new protective groups with orthogon-
ality start to be necessary for these materials as well. In this
which are rather costly. The development of inexpensive
4
5
Received: August 17, 2015
study, we focus on the protection of the carboxylic acid moiety.
The most common carboxylic acid-bearing synthetic polymers
Revised: September 26, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.macromol.5b01823
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Macromolecules
Article
Figure 1. Chemical structures and names of the main reagents used for the polymer syntheses: GTP initiator (MTS), chain transfer agent for RAFT
polymerization (CPDB), RAFT initiator (AIBN), and the monomers PyEMA, BzMA, and THPMA.
base-labile protective groups for carboxylic acid together with
the already available acid-labile counterparts would constitute a
powerful orthogonal protective pair for the important
carboxylic acid moiety.
distilled from CaH . The GTP catalyst, tetrabutylammonium
2
bibenzoate (TBABB), was synthesized by the reaction of tetrabutyl-
ammonium hydroxide and benzoic acid in water, following the
3
1
procedure of Dicker et al., and was kept under vacuum until use.
BzMA was passed through a basic alumina column to remove the
acidic impurities and the polymerization inhibitors, and it was
We recently showed that 2-(pyridin-2-yl)ethanol is a good
protecting group for PMAA repeating units, with lability under
mildly alkaline conditions (dilute aqueous sodium hydroxide
solution at room temperature), converting the ester to 2-
vinylpyridine (low molecular weight side product) and MAA
subsequently stirred over CaH (to remove the last traces of moisture
2
and protonic impurities) in the presence of added DPPH (free-radical
inhibitor) and stored in the refrigerator at ∼5 °C. BzMA was freshly
distilled under vacuum just before its use and was kept under a dry
argon atmosphere. The GTP initiator, MTS, was distilled just prior to
2
9
units. In addition to base lability, the above-mentioned 2-
pyridin-2-yl)ethyl polymeric ester exhibited thermolyzability
when exposed to 130 °C for a few hours either in the bulk or in
(
the polymerization, without being stirred over CaH or passed through
2
a basic alumina column because of the risk of hydrolysis. AIBN was
recrystallized twice from ethanol. All glassware was dried overnight at
2
9,30
solution.
Our previous reports proved the base and thermal
1
50 °C and assembled hot under dynamic vacuum prior to use.
lability of the 2-(pyridin-2-yl)ethyl methacrylate (PyEMA)
units only in its homopolymers and its diblock copolymers with
Synthesis of 2-(Pyridin-2-yl)ethyl Methacrylate (PyEMA).
29
The PyEMA monomer was prepared by the esterification of 2-
pyridin-2-yl)ethanol with 25% molar excess of methacryloyl chloride,
the relatively stable methyl methacrylate (MMA), styrene and
(
30
(
pyridin-2-yl)methyl methacrylate. In the present study, we
29,30
as detailed in our previous publications.
The yield in pure PyEMA
extend our work by combining PyEMA in ABC triblock
copolymers with the acid-labile tetrahydro-2H-pyran-2-yl
methacrylate (THPMA) and the hydrogenolysis-labile benzyl
methacrylate (BzMA), and prove full orthogonal deprotect-
ability between the PyEMA and the THPMA units. The
findings of this work may be of use in the development of new
monomer in the present synthesis was 87%. The purified PyEMA was
1
13
1
characterized using H and C NMR spectroscopy. H NMR (CDCl ,
3
δ): 1.80 ppm (s, CH CCH , 3 H), 3.09 ppm (t, −OCH CH −, 2
2
3
2
2
H), 4.45 ppm (t, −OCH
CH −, 2 H), 5.44 ppm (s, olefinic H trans to
2
2
CO , 1 H), 5.95 ppm (s, olefinic H cis to CO , 1 H), 7.09 ppm (1 H),
2
2
1
3
7
.24 ppm (1 H), 7.51 ppm (1 H), and 8.48 ppm (1 H). C NMR
4
,5
(CDCl , δ): 18.24 ppm (s, CH CCH , 1 C), 37.43 ppm (s,
3
2
3
sequence-controlled polymers.
−
OCH CH −, 1 C), 63.84 ppm (s, −OCH CH −, 1 C), 121.60 ppm
2
2
2
2
(
s, aromatic, 1 C), 123.43 ppm (s, aromatic, 1 C), 125.46 ppm (s,
EXPERIMENTAL SECTION
Materials and Methods. 2-(Pyridin-2-yl)ethanol (98%), meth-
acryloyl chloride (97%), methacrylic acid (MAA, 99%), 3,4-dihydro-
CH CCH , 1 C), 136.24 ppm (s, CH CCH , 1 C), 136.32 ppm
■
2
3
2
3
(s, aromatic, 1 C), 149.46 ppm (s, aromatic, 1 C), 158.12 ppm (s,
aromatic, 1 C) and 167.25 ppm (s, CO , 1 C).
2
Synthesis of Tetrahydro-2H-pyran-2-yl Methacrylate
THPMA). The THPMA monomer was prepared by the reaction of
2H-pyran (97%), benzyl methacrylate (BzMA, 96%), 1-methoxy-1-
(
trimethylsiloxy-2-methylpropene (MTS, 95%), 2-cyanoprop-2-yl
dithiobenzoate (97%), tetrabutylammonium hydroxide (40% w/w in
water), benzoic acid (99.5%), 1,4-dioxane (99.8%), 2,2-diphenyl-1-
MAA with a 100% excess of 3,4-dihydro-2H-pyran. In particular, 3,4-
dihydro-2H-pyran (21.51 mL, 19.84 g, 0.2358 mol), methacrylic acid
(10 mL, 10.15 g, 0.1179 mol), and a small amount of DPPH were
picrylhydrazyl hydrate (DPPH, 95%), calcium hydride (CaH , 90−
2
transferred to a 100 mL two-neck round-bottomed flask containing a
magnetic stirring bar. The solution was stirred at 65 °C, over a 48 h
period. The mixture was passed twice through a basic alumina column
to remove the unreacted and excess methacrylic acid and any other
protonic impurities. Then, the solvent was evaporated off to give pure
9
5%), basic alumina, potassium metal (99%), sodium deuteroxide (40
wt % in D O, 99.5 atom % D), and deuterium chloride (35 wt %
2
solution in D O, 99 atom % D) were purchased from Aldrich,
2
Germany. Synthesis grade triethylamine (≥99%), n-hexane (96%), and
tetrahydrofuran (THF, 99.8%) were obtained from Scharlau, Spain.
THF was also used as the mobile phase in chromatography (HPLC
grade) and as solvent (reagent grade) for one of the polymerizations
monomer in 60% yield. Finally, THPMA was stirred over CaH
presence of DPPH to remove all the moisture and the last traces of
in the
2
1
13
(
(
(
GTP). 2,2′-Azobis(isobutyronitrile) (AIBN, 95%), methanol
acidic impurities. THPMA was characterized using H and C NMR
1
99.9%), sodium hydroxide (NaOH, 99%), dimethyl sulfoxide
spectroscopy. H NMR (CDCl
−CH CH CH CH O−, 6 H), 1.95 ppm (s, CH
3.6−3.9 ppm (m, −OCH CH −, 2 H), 5.6 ppm (s, olefinic H trans to
CO , 1 H), 6.05 ppm (t, −O−CH−O−, 1 H), 6.15 ppm (s, olefinic H
cis to CO , δ): 18.1 ppm (s, CH , 1
, 1 H). 13C NMR (CDCl
CCH
C), 18.51 ppm (s, −CH CH CH CH O−, 1 C), 24.9 ppm (s,
3
, δ): 1.4−1.8 ppm (m,
DMSO, 99%), deuterated dimethyl sulfoxide (d -DMSO, 99.9%),
2
2
2
2
2
CCH , 3 H),
3
6
and deuterated chloroform (CDCl , 99.8%) were purchased from
2
2
3
Merck, Germany. Finally, sodium metal (98%) was from Fluka.
The solvent for GTP, THF, was purified by being refluxed in a
specially constructed still over a potassium−sodium benzophenone
complex (a deep purple color indicated an oxygen- and moisture-free
solvent). The solvent for RAFT polymerization, 1,4-dioxane, was
2
2
3
2
3
2
2
2
2
−CH CH CH CH O−, 1 C), 29.15 ppm (s, −CH CH CH CH O−,
1 C), 63.1 ppm (s, −CH CH CH CH O−, 1 C), 92.7 ppm (s, −O−
2
2
2
2
2
2
2
2
2
2
2
2
B
DOI: 10.1021/acs.macromol.5b01823
Macromolecules XXXX, XXX, XXX−XXX

Macromolecules
Article
−
1
CH−O−, 1 C), 125.8 ppm (s, CH CCH , 1 C), 136.4 ppm (s,
GPC, were M = 10 700 g mol (theoretically expected molecular
n
2
3
−1
CH CCH , 1 C), and 165.8 ppm (s, CO , 1 C).
weight = 6900 g mol ) and Đ = 1.34. Afterward, 1.45 mL of THPMA
(1.51 g, 8.85 mmol) and 1.69 mL of PyEMA (1.69 g, 8.85 mmol) were
added to the active BzMA -b-THPMA copolymer. After another 24
h of polymerization at 65 °C, monomer conversion, determined via H
NMR spectroscopy, was 100% for THPMA and 88% for PyEMA,
whereas the molecular weight characteristics of the resulting BzMA20-
b-THPMA -b-(THPMA -co-PyEMA ) terpolymer, as measured
2
3
2
Polymerizations. GTP and RAFT polymerization were used for
the polymer syntheses described in this study. The chemical structures
and names of the main reagents used for these syntheses are shown in
Figure 1.
20
20
1
GTP. The BzMA -b-PyEMA -b-THPMA triblock terpolymer was
5
5
5
synthesized by three-step sequential GTP. The polymerization
reaction was carried out in a round-bottomed glass flask thermostated
at −20 °C using an acetone−dry ice bath. The polymerization
exotherms were monitored by a digital thermometer and were used to
follow the progress of the reaction. The final concentration of the
terpolymer in the polymerization reaction was 30% w/v. The
experimental procedure followed for the preparation of the BzMA5-
b-PyEMA -b-THPMA triblock terpolymer is detailed below.
2
0
20
20
−1
using GPC, were Mn = 16 200 g mol (theoretically expected
−1
molecular weight = 13 300 g mol ) and Đ = 1.31. The terpolymer was
precipitated in n-hexane and dried in vacuo for 48 h.
Removal of the Protecting Groups. Alkaline Hydrolysis of the
PyEMA Units. The PyEMA units in the BzMA20-b-THPMA20-b-
(THPMA20-co-PyEMA20) triblock terpolymer were hydrolyzed
selectively in a DMSO/MeOH (5:3 v/v) mixture in the presence of
sodium hydroxide, at room temperature. In particular, 0.5 g of the
original ABC triblock terpolymer (0.72 mequiv of PyEMA units) was
dissolved in 8 mL of DMSO/MeOH (5:3 v/v), and to the resulting
solution was added 0.2 g of solid NaOH (5 mmol). After 24 h, DMSO,
MeOH, and the produced 2-vinylpyridine were distilled off in the
vacuum line. The product was purified from NaOH by dialysis against
water for 3 days, using dialysis tubing with a 3000 g mol− molecular
weight cutoff. The external water was changed twice a day. Then, the
purified BzMA -b-THPMA -b-(THPMA -co-MAA ) terpolymer
5
5
A catalytic amount of TBABB (∼20 mg, ∼40 μmol, ∼3% mol
relative to the initiator) was transferred to a 50 mL round-bottomed
flask containing a stirring bar. The flask was immediately sealed with a
rubber septum, and it was purged with dry argon. Subsequently, 9.8
mL of freshly distilled THF was transferred into the flask via a glass
syringe, followed by the addition of 0.3 mL of the MTS initiator (0.258
g, 1.48 mmol). Then, 1.25 mL of BzMA (1.30 g, 7.4 mmol) was slowly
added using a glass syringe, producing an exotherm (−20 to −17 °C).
The exotherm abated within 5 min, and samples (2 × 0.1 mL) were
withdrawn for analyses by gel permeation chromatography (GPC)
1
2
0
20
20
20
was isolated by freeze-drying from water. A similar experiment was
performed on smaller scale using deuterated solvents. In this case, H
−
1
1
(
GPC number-average molecular weight = Mn = 1570 g mol
compared to the theoretical value expected on the basis of the
monomer-initiator feed ratio of 980 g mol ; molecular weight
NMR spectroscopy was performed without the removal of the volatile
components, so that 2-vinylpyridine could remain in the solvent and
be seen in the spectrum.
−1
dispersity = Đ = M /M = 1.37; M is the weight-average molecular
w
n
w
1
weight) and H NMR spectroscopy (complete monomer conversion;
degree of polymerization, DP, determined to be 5 by end-group
analysis, identical to the theoretically expected value). Afterward, 1.42
mL of PyEMA (1.42 g, 7.4 mmol) was slowly added using a glass
syringe, producing an exotherm (−20 to −17 °C). The exotherm
abated within 5 min, and samples (2 × 0.1 mL) were extracted for
Acid Hydrolysis of the THPMA Units. The THPMA units in the
BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymer
20
20
20
20
were hydrolyzed selectively in a DMSO/MeOH (1:1 v/v) mixture in
the presence of hydrochloric acid, at room temperature. In particular,
0.5 g of the original ABC triblock terpolymer (1.32 mequiv of
THPMA units) was dissolved in 10 mL of DMSO/MeOH (1:1 v/v),
and to the resulting solution were added 5 drops of HCl (35%, 6.7
mmol). After 24 h, DMSO, MeOH, and the produced 3,4-dihydro-2H-
pyran were distilled off in the vacuum line. The product was freed
from HCl by dialysis against water for 3 days, using the same type of
dialysis tubing as mentioned above. The external water was again
changed twice a day, and the purified BzMA -b-MAA -b-(MAA -co-
−1
analyses by GPC (GPC Mn = 2060 g mol compared to the
−1
1
theoretically expected value of 1940 g mol ; Đ = 1.40) and H NMR
spectroscopy (100% monomer conversion; PyEMA content in
copolymer = 50.0 mol % compared to 50.0 mol % expected from
the comonomer feed ratio and given complete comonomer
conversion). Afterward, 1.22 mL of THPMA (1.26 g, 7.4 mmol)
was slowly added using a glass syringe, producing an exotherm (−20
to −18 °C). The exotherm abated within 10 min, 0.5 mL of methanol
was added to terminate the polymerization, and samples (2 × 0.1 mL)
20
20
20
PyEMA ) terpolymer was finally isolated by freeze-drying from water.
20
Alkaline Hydrolysis of the PyEMA Units after the Acid Hydrolysis
of the THPMA Units. 0.2 g of the purified and dried BzMA -b-MAA -
2
0
20
−
1
were again obtained for analyses by GPC (GPC M = 3160 g mol
b-(MAA -co-PyEMA ) (0.29 mequiv of PyEMA units) terpolymer
n
20 20
−1
compared to the theoretically expected value of 2790 g mol ; Đ =
resulting from the conversion of the THPMA to MAA units was
dissolved in 3.2 mL of a DMSO/MeOH (5:3 v/v) mixture, and to the
resulting solution was added 0.08 g of solid NaOH (2 mmol). After 24
h, DMSO, MeOH, and the produced 2-vinylpyridine were distilled off
in the vacuum line. The product was freed from NaOH by dialysis
against water for 3 days and was finally freeze-dried from water.
Acid Hydrolysis of the THPMA Units after the Alkaline Hydrolysis
of the PyEMA Units. 0.2 g of the purified and dried BzMA20-b-
THPMA20-b-(THPMA20-co-MAA20) (0.53 mequiv of THPMA units)
terpolymer resulting from the conversion of the PyEMA to MAA units
was dissolved in 4 mL of a DMSO/MeOH (1:1 v/v) mixture, and to
the resulting solution were added 5 drops of HCl (35%, 6.7 mmol).
After 24 h, DMSO, MeOH, and the produced 3,4-dihydro-2H-pyran
were distilled off in the vacuum line. The product was freed from HCl
by dialysis against water for 3 days and was finally freeze-dried from
water.
1
1
.36) and H NMR spectroscopy (complete monomer conversion;
THPMA content in the triblock terpolymer = 33.3 mol % compared to
3.3 mol % expected from the comonomer feed ratio and given
3
complete comonomer conversion).
RAFT Polymerization. The BzMA -b-THPMA -b-(THPMA -co-
20
20
20
PyEMA ) triblock terpolymer was synthesized by a three-step
20
sequential RAFT polymerization. AIBN (0.0454 g, 0.2766 mmol)
and 2-(cyanoprop-2-yl) dithiobenzoate (CPDB) RAFT CTA (0.0979
g, 0.4426 mmol) were dissolved in 1,4-dioxane (1.45 mL) and
transferred to a 50 mL round-bottomed flask, fitted with a glass valve,
containing BzMA (1.50 mL, 1.56 g, 8.85 mmol) and a magnetic
stirring bar. This resulted in a monomer solution at a concentration of
3
.0 M. The system was degassed by three freeze−pump−thaw cycles
and was subsequently placed in an oil bath at 65 °C for 24 h.
Monomer conversion, measured using H NMR spectroscopy, was
1
1
00%, whereas the poly(BzMA) molecular weight characteristics, as
Hydrogenolysis of the BzMA Units. 23 mg of the purified and dried
BzMA20-b-MAA20-b-MAA40 (0.06 mequiv of BzMA units) copolymer
resulting from the sequential alkaline and acidic hydrolyses of the
original terpolymer was dissolved in 10 mL of an ethyl acetate/MeOH
(9:1 v/v) mixture. Subsequently, 23 mg of Pd/C (10%) catalyst was
added to the solution and was left for hydrogenolysis for 3 weeks
under hydrogen atmosphere in a two-neck round-bottomed flask fitted
with a balloon. The balloon was changed every 2 days, and the system
was refilled with hydrogen. After the completion of the hydrogenolysis
−1
measured using GPC, were M = 6880 g mol (theoretically expected
molecular weight = 3500 g mol ) and Đ = 1.30. Afterward, 1.45 mL
of THPMA (1.51 g, 8.85 mmol) and Et N (0.2 mL), in order to
protect THPMA from spontaneous hydrolysis, were added to the
solution of poly(BzMA). The system was left at 65 °C for another 24
h, at which point H NMR spectroscopy indicated that monomer
conversion reached 100%, whereas the molecular weight characteristics
of the produced BzMA -b-THPMA copolymer, as measured using
n
−1
3
32
1
20
20
C
DOI: 10.1021/acs.macromol.5b01823
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Macromolecules
Article
Scheme 1. Addition Sequences Followed for the Preparation of the Two ABC Triblock Terpolymers
Figure 2. GPC traces of (a) the BzMA -b-PyEMA -b-THPMA and (b) the BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymers
5
5
5
20
20
20
20
along with those of their precursors.
reaction, the mixture was filtered, and the product was isolated by
distillation of the solvents and toluene (hydrogenolysis side product)
in the vacuum line.
DSC. Differential scanning calorimetry (DSC) was performed using
a Q1000 Thermal Analysis Instruments (TA) differential scanning
calorimeter. Sample amounts of 0.5−2.0 mg were prepared in
hermetically sealed DSC pans. The temperature range covered was
from 40 to 275 °C.
TGA. Thermal gravimetric analysis (TGA) was performed on a
Q500 TA thermogravimetric analyzer using ceramic pans. The
temperature range from 40 to 600 °C was covered, whereas sample
amounts of around 10 mg were loaded.
Characterization of Copolymer Self-Assembly in Water. The
two amphiphilic BzMA−MAA diblock copolymers obtained from the
thermolysis of the two ABC triblock terpolymers were characterized in
terms of their aqueous solution micellization properties in alkaline (pH
Thermolysis of the PyEMA and the THPMA Units. The PyEMA
and the THPMA units in the BzMA -b-PyEMA -b-THPMA and the
5
5
5
BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymers
20
20
20
20
were cleaved by thermolysis at 130 °C for 6 h. To this end, ∼20 mg of
each ABC triblock terpolymer was transferred in to a small (capacity of
2
mL) glass vial which was placed in a vacuum oven at 130 °C. After 6
h, the heating in the vacuum oven was stopped, the vial was allowed to
cool down in the vacuum oven, and its contents were analyzed using
1
H NMR spectroscopy in d -DMSO.
6
Polymer Characterization. Gel Permeation Chromatography.
The molecular weight distributions (MWDs) of all the polymers were
recorded using gel permeation chromatography (GPC), from which
=
11.5) water in which they were soluble. To this end, dynamic and
static light scattering and atomic force microscopy were employed.
Sample preparation involved multiple filtering of the aqueous
copolymer solutions through syringe microfilters with pore diameter
of 0.45 μm.
the M and Đ values, as well as the values of the molecular weights at
n
the peak maximum, M , were calculated. A single Polymer
p
Laboratories PL-Mixed “D” column (bead size = 5 μm; pore sizes =
3
4
1
00, 500, 10 , and 10 Å) was used for sample analysis. The mobile
Dynamic and Static Light Scattering (DLS/SLS). The light
scattering experiments were performed at room temperature using
an ALV/CGS-3 compact goniometer system scattering spectropho-
tometer, equipped with a 22 mW uniphase helium−neon laser
emitting at 632.8 nm, two APD detectors, and an ALV-7004 digital
correlator. The scattered light was detected at 90° for the DLS
measurements, while for the SLS measurements the scattered light was
detected in the angular range from 30° to 150° at 10° intervals. For
DLS, only one copolymer concentration was employed, 1.00% w/v,
whereas for SLS, a range of copolymer concentrations was utilized,
from 0.33 to 1.00% w/v.
phase was THF, delivered using a Waters 515 isocratic pump at a flow
−1
rate of 1 mL min . The refractive index (RI) signal was measured
using a Polymer Laboratories ERC-7515A RI detector. The calibration
curve was based on nine narrow molecular weight (800, 2220, 6400,
−1
1
2 600, 23 500, 41 400, 84 300, 201 000, and 342 000 g mol ) linear
polyMMA standards also supplied by Polymer Laboratories.
NMR Spectroscopy. 300 and 500 MHz Avance Bruker NMR
spectrometers, equipped with Ultrashield magnets, were used to
1
13
acquire the H and C NMR spectra of all the synthesized monomers
1
in CDCl and the H NMR spectra of all the polymers in CDCl or d -
3
3
6
DMSO.
D
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Table 1. Molecular Weight and Composition Characteristics of the Polymers Synthesized Using GTP and RAFT Polymerization
1
Results from GPC
Results from H NMR spectroscopy
polymer composi-
tion (mol %)
theoretical molecular
Mp
Mn
monomer
conversion (%)
weight (g mol−
1
)
(g mol−1)
(g mol−1)
Đ
BzMA
PyEMA
polymer structure
a
BzMA5
980
1940
2790
3500
6900
2170
3090
1570
2060
1.37
1.40
1.29
1.30
1.34
1.38
100
100
100
100
100
100.0
50.0
33.3
100.0
50.0
33.5
0.0
50.0
33.3
0.0
a
BzMA -b-PyEMA5
5
a
5
BzMA -b-PyEMA -b-THPMA
3800
3700
5
5
b
BzMA20
9500
6880
b
BzMA -b-THPMA
20
16700
21100
10700
13600
0.0
2
0
b
c
BzMA -b-THPMA -b-(THPMA -co-PyEMA )
13700
94
20.2
2
0
20
20
20
a
b
c
Synthesized by GTP. Synthesized by RAFT polymerization. Conversion of PyEMA was 88% and that of THPMA was 100%.
Scheme 2. Cleavage Sequences Followed for the Stepwise and Selective Deprotection of the BzMA -b-THPMA -b-(THPMA -
2
0
20
20
a
co-PyEMA ) Triblock Terpolymer All the Way to MAA
20
80
a
(
i) HCl in DMSO/MeOH (1:1 v/v); (ii) NaOH(s) in DMSO/MeOH (5:3 v/v); (iii) vacuum oven at 130 °C for 6 h; (iv) H in ethyl acetate/
2
MeOH (9:1 v/v) and Pd/C catalyst.
Atomic Force Microscopy (AFM). The AFM experiments were
performed using a Cypher ES Asylum Research/Oxford Instruments
atomic force microscope in AC (“tapping”) mode in air at room
temperature, using ACT silicon tips from Applied Nanostructures
protons which would lead to GTP termination. Scheme 1
illustrates the addition sequences followed for the syntheses of
the two ABC triblock terpolymers via the two polymerization
methods.
−1
(
frequency 300 kHz, tip radius <10 nm, spring constant 37 N m ).
Figure 2 shows the GPC traces of the terpolymers and their
precursors, while Table 1 summarizes the results calculated
from these GPC traces. These results were the M , the M , and
Dilute aqueous copolymer solutions, 0.01% w/w, were deposited on a
fresh mica surface using spin-coating.
n
p
the Đ values of the polymers. The theoretical molecular
weights, calculated from the monomer-to-initiator ratio in the
polymerization feed and taking into account monomer
conversion, are also listed in the table. Furthermore, the
content in each type of unit in the terpolymers and their
RESULTS AND DISCUSSION
■
Polymer Design and Synthesis. Polymer preparation in
the present study was successfully performed using two
controlled polymerization methods: GTP and RAFT polymer-
ization. This demonstrated that both methods can accom-
modate the demanding three-stage syntheses, involving two
rather labile monomers whose premature deprotection during
the course of the polymerization would compromise the quality
of the final polymer products. GTP was used to synthesize a
rather small ABC triblock terpolymer with short blocks
comprising 5 units each, while RAFT polymerization allowed
the synthesis of a larger terpolymer with 20 or more units in
each block. The most stable BzMA was introduced as the first
block in both terpolymers. Since PyEMA has a large tendency
to thermolyze, it was introduced as the last block, mixed with a
further equimolar amount of THPMA, in the terpolymer made
by RAFT polymerization (polymerization temperature was 65
1
precursors, as calculated from the H NMR spectra, are also
listed in the table. The table shows that monomer conversion
was quantitative or near-quantitative in all cases, the polymer
composition and molecular weights were close to the expected,
and the molecular weight dispersities were reasonably low, 1.40
or lower.
Stepwise Removal of the Protecting Groups. Scheme 2
shows the various routes followed for the sequential and
selective deprotection of BzMA -b-THPMA -b-(THPMA -
20
20
20
co-PyEMA ). The PyEMA units are labile in an alkaline
20
environment, whereas the THPMA units are labile under acidic
conditions. PolyBzMA can be converted to polyMAA via
catalytic hydrogenolysis using a palladium catalyst. According
to Scheme 2, first, by exposing the terpolymer to acidic
conditions (i), its THPMA units would be converted to MAA
units, while the PyEMA and the BzMA units are preserved. If
°
C). In contrast, THPMA was chosen to be polymerized last in
GTP, taking into account the large tendency of this monomer
to hydrolyze even at room temperature, yielding carboxylic acid
E
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1
Figure 3. H NMR spectra in d -DMSO of (a) the original BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymer (black), (b) the
6
20
20
20
20
same terpolymer after acidic hydrolysis (red), and (c) after acidic and alkaline hydrolyses (blue).
the resulting terpolymer is now subjected to alkaline hydrolysis
conditions (ii), the PyEMA units would be cleaved to MAA
units, leading to the formation of a BzMA−MAA diblock
copolymer. If this copolymer is subjected to hydrogenolysis
oxymethylene protons “j” at 4.3 ppm and the adjacent
methylene protons “k” at 3.0 ppm of the PyEMA unit were
preserved in spectrum (b). Subsequent treatment of this acidic
hydrolysis product with NaOH resulted in the removal of the
side groups of the PyEMA units as evidenced by the absence of
(iv), it would be converted to an MAA homopolymer.
1
Alternatively, the terpolymer could be first exposed to alkaline
hydrolysis conditions (ii), which would convert its PyEMA
units to MAA units, without affecting the THPMA or the
BzMA units. Then, the resulting terpolymer could be subjected
to acidic hydrolysis conditions (i), which would convert the
THPMA units to MAA units, yielding again the BzMA−MAA
diblock copolymer which could undergo hydrogenolysis (iv) to
polyMAA. The PyEMA and the THPMA units in the original
terpolymer could also be simultaneously (and nonselectively)
converted to MAA units thermally (iii), without affecting the
BzMA units. The product obtained after each of the above
their “j” and “k” protons (blue circle) in the H NMR spectrum
in Figure 3c. Figure S1 in the Supporting Information shows
the TGA and the DSC thermograms of this terpolymer after
acidic hydrolysis and after acidic and alkaline hydrolyses,
together with those of the original triblock terpolymer. These
thermograms were consistent with the structures of these three
polymers. In particular, the percentage mass loss at ∼200 °C in
the TGA traces decreased in the order BzMA -b-THPMA -b-
20
20
(THPMA -co-PyEMA ) > BzMA -b-MAA -b-(MAA -co-
2
0
20
20
20
20
PyEMA ) > BzMA -b-MAA -b-MAA , as expected. Sim-
20
20
20
40
ilarly, the intensity of the endothermic peaks in the range of
150−250 °C in the DSC traces decreased in the same order as
above, again qualitatively consistent with the claimed structures.
1
processing steps was characterized using H NMR spectrosco-
py, TGA, and DSC, and the results are presented in the
following sections.
1
Similarly, Figure 4 displays the H NMR spectra of the
Sequential Application of Hydrolyses and Hydro-
genolysis. Figure 3 shows the H NMR spectra of the polymer
polymer products obtained by processing the original triblock
terpolymer now first under alkaline hydrolysis conditions, then
under acidic hydrolysis conditions, and, finally, under hydro-
1
products obtained by subjecting the original terpolymer first to
1
1
acidic hydrolysis conditions and then to alkaline. The H NMR
genolysis conditions. The H NMR spectrum of the original
spectrum of the original BzMA -b-THPMA -b-(THPMA -co-
BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock ter-
2
0
20
20
20
20
20
20
1
PyEMA ) triblock terpolymer is also presented in Figure 3.
polymer is shown in the figure, too. By examining H NMR
spectra (a) and (b) in Figure 4, the result of subjecting the
terpolymer to alkaline hydrolysis conditions can be inferred.
Compared to spectrum (a), spectrum (b) lacks the peak of the
oxymethylene protons “j” at 4.3 ppm and the peak of the
adjacent methylene protons “k” at 3.0 ppm in the side group of
20
Comparing spectra (a) and (b) in the figure, it can be seen that
upon treatment with acid the methine proton “e” of the
THPMA unit at 5.8 ppm disappeared in spectrum (b) (red
circle), due to the removal of the tetrahydropyranyl ring. This
did not affect the PyEMA units as their characteristic
F
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1
Figure 4. H NMR spectra in d -DMSO of (a) the original BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymer (black), (b) the
6
20
20
20
20
same terpolymer after alkaline hydrolysis (blue), (c) the same terpolymer after alkaline and acidic hydrolyses (red), and (d) after alkaline and acidic
hydrolyses as well as catalytic hydrogenolysis (green).
Figure 5. DSC thermograms of (a) the homopolymers of PyEMA, THPMA, and BzMA, (b) the BzMA -b-PyEMA -b-THPMA triblock terpolymer,
5
5
5
and (c) the BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymer.
20
20
20
20
the PyEMA unit (blue circles). At the same time, the peak of
the vinyl protons “o” at 5.5 ppm and “p” at 6.2 ppm of 2-
vinylpyridine appeared in spectrum (b), due to the conversion
of the PyEMA unit to a MAA unit and 2-vinylpyridine. By
subsequently subjecting the thus-obtained terpolymer to acidic
hydrolysis conditions, this led to the disappearance of the
methine proton “e” (red circle) due to the hydrolysis of the
THPMA units and their conversion to MAA units. Finally,
catalytic hydrogenolysis of this hydrolysis product resulted in
the removal of the benzylic protons “c” at 4.9 ppm (green
circle) and the conversion of the BzMA units to MAA units.
The BzMA -b-PyEMA -b-THPMA triblock terpolymer,
treatment, respectively, converting the original BzMA -b-
5
PyEMA -b-THPMA5 triblock terpolymer to a BzMA -b-
5
5
MAA diblock copolymer. However, due to the low molecular
10
weight of this polymer, purification after each processing step
using dialysis was impossible. Thus, the hydrogenolysis of the
BzMA units in the BzMA−MAA diblock copolymer was not
1
attempted. Figure S2 shows the H NMR spectrum of the
1
original ABC triblock terpolymer prepared by GTP and the H
NMR spectra of the products obtained after each processing
step.
Thermal Deprotection of PolyPyEMA and Poly-
THPMA. Figure 5 shows the DSC thermograms of the
PyEMA, the THPMA and the BzMA homopolymers, and
those of the two ABC triblock terpolymers. All major peaks
were endothermic and irreversible (not reproduced upon the
5
5
5
obtained by GTP, was also subjected to alkaline and acidic
hydrolyses. The product obtained after alkaline or acidic
treatment was subsequently subjected to acidic or alkaline
G
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Figure 6. TGA thermograms of (a) the homopolymers of PyEMA, THPMA, and BzMA, (b) the BzMA -b-PyEMA -b-THPMA triblock terpolymer,
5
5
5
and (c) the BzMA -b-THPMA -b-(THPMA -co-PyEMA ) triblock terpolymer.
20
20
20
20
1
Figure 7. H NMR spectra of (a) the original BzMA -b-PyEMA -b-THPMA triblock terpolymer in CDCl (black) and (b) the same terpolymer in
5
5
5
3
d6-DMSO after thermolysis at 130 °C under vacuum (red).
second heating cycle), suggestive of their origin in chemical
reactions, and took place between 150 and 250 °C. In the case
of the PyEMA homopolymer, the main endothermic peak was
located at 180 °C, followed by a shoulder at 210 °C, both of
which were related to the cleavage of the PyEMA unit. In the
case of the THPMA homopolymer, the main peak was at 160
polyPyEMA thermolysis appearing as a much weaker
endotherm at 180 °C.
Figure 6 shows the TGA thermograms of the PyEMA, the
THPMA and the BzMA homopolymers and those of the two
ABC triblock terpolymers. In the case of the PyEMA
homopolymer, the weight loss started at ∼170 °C, manifesting
side-group removal, consistent with DSC, followed by a further
weight loss at ∼400 °C and higher temperature due to
29
°C, at slightly lower temperature than that of the PyEMA
homopolymer but of much higher intensity (enthalpy of
reaction) than that of PyEMA, and followed by a less intense
peak at 220 °C, manifesting the conversion of the THPMA to
MAA units. In the case of the BzMA homopolymer, no thermal
response was observed up to 250 °C, but an endotherm was
initiated at 270 °C. This was interestingly due to the
29
complete backbone decomposition. In the case of the
THPMA homopolymer, the weight loss started at ∼140 °C,
again in agreement with DSC, followed by a further weight loss
at ∼400 °C and higher temperature owing to backbone
destruction. In the case of the BzMA homopolymer, the weight
loss was due to the depolymerization of the BzMA units
33
depolymerization of polyBzMA, inferred from the analysis
(
Figure S3). This change started at ∼250 °C, also in agreement
1
of the material recovered from the DSC pan using H NMR
with the DSC data, and was completed just below ∼400 °C.
The TGA thermograms of the two ABC triblock terpolymers
were similar to each other, and, as the DSC thermograms, they
seemed to result from linear superpositions of the TGA
thermograms of the three constituting homopolymers. In
particular, the TGA thermograms of the terpolymers showed
initial weight losses due to the cleavage of the side groups of the
PyEMA and the THPMA units between 150 and 200 °C, with
spectroscopy (Figure S3).
The DSC thermograms of the two ABC triblock terpolymers
were very similar to each other and exhibited all endothermic
peaks displayed by the PyEMA and the THPMA homopol-
ymers between 150 and 250 °C. However, these thermograms
were dominated by the more intense main peak of the
thermolysis of polyTHPMA at 160 °C, with the main peak of
H
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Figure 8. AFM images and distributions of the diameters of the spherical micelles formed by the BzMA -b-MAA10 and the BzMA -b-MAA
60
5
20
amphiphilic diblock copolymers in water.
Table 2. Micellar Characteristics of the Linear Amphiphilic BzMA−MAA Diblock Copolymers Determined Using Light
Scattering and AFM
SLS
N = Mwaggregate/Mnunimer
DLS
AFM
maximum theoretical
Mnunimer (g mol−1
)
Mwaggregate (g mol−1
)
D (nm)
h
D (nm)
diameter (nm)
a
polymer structure
BzMA -b-MAA
1840
8470
2.151 × 104
2.684 × 106
12
29
47
67
7.56
5
10
BzMA -b-MAA
60
320
154
40.32
20
a
Calculated as twice the chain contour length (length of fully extended polymer chain); the contour length was calculated as the product of the
34
degree of polymerization times 0.252 nm, the contribution of one monomer repeating unit to the fully stretched chain length.
complete weight loss occurring between 350 and 450 °C due to
backbone decomposition. The dashed horizontal lines indicate
the theoretical weight percent remaining after complete side
group removal and calculated on the basis of thorough loss of
triblock terpolymers were amphiphilic and therefore formed
micelles in aqueous solution. Preliminary characterization of the
size of these micelles was performed using light scattering and
AFM. AFM images of the micelles formed by the two
copolymers are displayed in Figure 8, whereas a summary of
all results, both from AFM and light scattering, is provided in
Table 2. Figure 8 shows that the micelles formed were spherical
and rather monodisperse. Furthermore, the micelles formed by
the larger copolymer were clearly larger than those formed by
the smaller, as expected.
2
-vinylpyridine and 3,4-dihydro-2H-pyran from the ABC
triblock terpolymers. For both terpolymers, there was good
agreement between experimental and theoretical weight
percentage of polymer left following thermal side group
removal at ∼200 °C.
1
Figure 7 shows the H NMR spectrum of the thermally
deprotected BzMA -b-PyEMA -b-THPMA triblock terpolymer
Table 2 lists the average diameters of the adsorbed micelles,
D, formed by the two copolymers, determined using AFM.
Both diameters were larger than the diameters calculated from
the chain dimensions, listed in the last column of the table. This
can be attributed to micellar widening due to flattening upon
adsorption, and also to the “tip effect” (tip diameter, ∼10 nm,
included in the determined size), particularly in the case of the
smaller micelles. Furthermore, formation of multimicellar
aggregates cannot be totally excluded.
5
5
5
(
7
Figure 7b) along with that of the original terpolymer (Figure
a). In this case, thermal deprotection was performed in a
vacuum oven at 130 °C only for 6 h to avoid undesirable
anhydride formation. The peaks due to the side groups of the
PyEMA and the THPMA units at 4.3 and 5.8 ppm, respectively
(red circles), were totally absent from the spectrum of the
thermolyzed sample, confirming the completeness of side group
removal.
Micelle Formation in Water. The BzMA−MAA diblock
copolymers obtained after the thermolysis of the two ABC
Table 2 also presents the results from light scattering, which
are consistent with those from AFM. The hydrodynamic
I
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diameters, D , the absolute weight-average molecular weights,
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, and the micellar aggregation numbers, N, calculated
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by dividing Mw
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by the single-chain number-average
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, were consistently larger for the
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CONCLUSIONS
■
Three different forms of protected MAA, PyEMA, THPMA,
and BzMA, were combined together in two ABC triblock
terpolymers: one prepared by RAFT polymerization and the
other by GTP. The alkaline hydrolysis of the PyEMA units and
the acidic hydrolysis of the THPMA units were mutually
orthogonal and could be completed within a few hours.
Furthermore, the catalytic hydrogenolysis of the BzMA units,
requiring a few weeks, allowed the quantitative conversion of all
the monomer repeating units of the ABC triblock terpolymers
to MAA units. Finally, the PyEMA and the THPMA units could
also be converted to MAA units thermally, without affecting the
BzMA units, forming linear amphiphilic BzMA−MAA diblock
copolymers, whose amphiphilicity led to aqueous solution
micellization which was studied using atomic force microscopy
and light scattering.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.macro-
mol.5b01823.
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AUTHOR INFORMATION
Corresponding Author
E-mail: costasp@ucy.ac.cy (C.S.P.).
■
*
(
̈
̈
(
Notes
Chemistry; Academic Press: New York, 1999.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
(23) Kang, M.; Moon, B. Macromolecules 2009, 42, 455−458.
■
(
24) Zhao, H.; Sterner, E. S.; Coughlin, E. B.; Theato, P.
This work was cofunded by the European Regional Develop-
ment Fund (ERDF) and the Republic of Cyprus (RoC)
through the Cyprus Research Promotion Foundation (CRPF)
within the infrastructure project NEA YPODOMH/NEKYP/
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311/27 which also enabled the purchase of the AFM and the
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project NEA YPODOMH/NEKYP/0308/02 (also cofunded
by the ERDF and the RoC through CRPF) and the A. G.
Leventis Foundation for helping establish the NMR infra-
structure at the University of Cyprus. Finally, we thank the
following colleagues at the University of Cyprus for their
assistance in various aspects of this work: Dr. K. S. Pafiti
2005, 41, 1569−1575.
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(
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■
(
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